Sunday, 5 July 2015

IMMUNE SUPPRESSION OF BORRELIA BURGDORFERI

Suppression of Long-Lived Humoral Immunity Following Borrelia burgdorferi Infection



Abstract


Lyme Disease caused by infection with Borrelia burgdorferi is an emerging infectious disease and already by far the most common vector-borne disease in the U.S. Similar to many other infections, infection with Bburgdorferi results in strong antibody response induction, which can be used clinically as a diagnostic measure of prior exposure. However, clinical studies have shown a sometimes-precipitous decline of such antibodies shortly following antibiotic treatment, revealing a potential deficit in the host’s ability to induce and/or maintain long-term protective antibodies. This is further supported by reports of frequent repeat infections with B.burgdorferi in endemic areas. The mechanisms underlying such a lack of long-term humoral immunity, however, remain unknown. We show here that Bburgdorferi infected mice show a similar rapid disappearance of Borrelia-specific antibodies after infection and subsequent antibiotic treatment. This failure was associated with development of only short-lived germinal centers, micro-anatomical locations from which long-lived immunity originates. These showed structural abnormalities and failed to induce memory B cells and long-lived plasma cells for months after the infection, rendering the mice susceptible to reinfection with the same strain ofBburgdorferi. The inability to induce long-lived immune responses was not due to the particular nature of the immunogenic antigens of Bburgdorferi, as antibodies to both T-dependent and T-independent Borrelia antigens lacked longevity and B cell memory induction. Furthermore, influenza immunization administered at the time of Borrelia infection also failed to induce robust antibody responses, dramatically reducing the protective antiviral capacity of the humoral response. Collectively, these studies show that Bburgdorferi-infection results in targeted and temporary immunosuppression of the host and bring new insight into the mechanisms underlying the failure to develop long-term immunity to this emerging disease threat.


Author Summary


Infections with the Lyme Disease agent, Borrelia burgdorferi, often fail to generate long-term protective immunity. We show here that this is because the immune system of the Borrelia-infected host generates only short-lived, structurally abnormal and non-functional germinal centers. These germinal centers fail to induce memory B cells and long-lived antibody-producing plasma cells, leaving the host susceptible to reinfection with Bb. This inability to induce long-term immunity was not due to the nature of Borrelia antigens, as even T-dependent antigens of Borrelia were unable to induce such responses. Moreover, influenza vaccine antigens, when applied during Borrelia-infection, failed to induce strong antibody responses and immune-protection from influenza challenge. This data illustrate the potent, if temporal, immune suppression induced by Borrelia-infection. Collectively, the data reveal a new mechanism by which Bburgdorferi subverts the adaptive immune response.

Monday, 29 June 2015

BARTONELLOSIS - ONE HEALTH - AN EMERGING INFECTIOUS DISEASE




Bartonellosis: One health perspectives on an emerging infectious disease

Published on Sep 10, 2014
Ian Beveridge Memorial Lecture 2014 by Professor Ed Breitschwerdt, DVM, is Professor of Medicine and Infectious Diseases at the Center for Comparative Medicine and Translational Research, College of Veterinary Medicine North Carolina State University Raleigh, North Carolina, USA.

Earlier posts on Bartonella 


Sunday, 28 June 2015

BORRELIA OF RELAPSING FEVER TYPE IDENTIFIED IN A TICK IN AUSTRALIA

Inhibition of the endosymbiont "Candidatus Midichloria mitochondrii" during 16S rRNA gene profiling reveals potential pathogens in Ixodes ticks from Australia.


' However, bacteria of medical significance were detected in I. holocyclus ticks, including a Borrelia relapsing fever group sp., Bartonella henselae, novel "Candidatus Neoehrlichia" spp., Clostridium histolyticum, Rickettsia spp., and Leptospira inadai.'

http://www.ncbi.nlm.nih.gov/pubmed/26108374

http://www.parasitesandvectors.com/content/pdf/s13071-015-0958-3.pdf

'Professor Peter Irwin and his colleagues have released the findings from research at Murdoch University. The results have huge implications for the requirement and potential of future research in Australia. Whilst only one tick species (I Holocyclus - aka Paralysis tick) was examined in this study - Borrelia of a relapsing fever species (unidentified) not before found in Australia was discovered. As was numerous other pathogens (Bartonella henselae, novel “Candidatus Neoehrlichia” spp., Clostridium histolyticum, Rickettsia spp., and Leptospira inadai).

What does this mean for Australian Lyme Borreliosis & Co Patients?? In short – It is BIG – and it speaks volumes to the requirements for further urgent research looking at the 70or so other species of ticks in Australia, and the infections they carry. With thousands suffering – Lets hope the Government is listening and provides research funds – and advances plans to put into place better testing and treatment for those chronically ill' 

https://www.facebook.com/134506933379413/photos/a.137124456450994.31458.134506933379413/468254026671367/?type=1&fref=nf&pnref=story


Tuesday, 9 June 2015

TICK TRANSMITTED BORRELIA - NEGATIVE TESTS -COULD IT BE MIYAMOTOI?

Borrelia miyamotoi Disease in the Northeastern United StatesA Case Series ONLINE FIRST

Philip J. Molloy, MD; Sam R. Telford III, ScD; Hanumara Ram Chowdri, MD; Timothy J. Lepore, MD; Joseph L. Gugliotta, MD; Karen E. Weeks, BS; Mary Ellen Hewins, BS; Heidi K. Goethert, ScD; and Victor P. Berardi
Conclusion: Patients with BMD presented with nonspecific symptoms, including fever, headache, rigors, myalgia, and arthralgia. Laboratory confirmation of BMD was possible by PCR on blood from acutely symptomatic patients who were seronegative at presentation. Borrelia miyamotoi may be an emerging tickborne infection in the northeastern United States.

Borrelia miyamotoi: The Newest Infection Brought to Us by Deer Ticks ONLINE FIRST

Peter J. Krause, MD; and Alan G. Barbour, MD

http://annals.org/article.aspx?articleid=2301403

Just some of the points raised - 

Acquisition of Borrelia Miyamotoi from unfed larval ticks is possible because of transovarial transmission of the pathogen from an infected female.

Human to human transmission by blood transfusion is theoretically possible 

A rash was present in only 8% and none described as Erythema Migrans

The diagnosis of Borrelia Miyamotoi in this case series was based on PCR  testing and subsequent sequencing.

To date no Borrelia Miyamotoi tests have been approved by US FDA.

A Wright or Giemsa-stained blood smear is a routinely performed procedure which might reveal Borrelia Miyamotoi spirochetes in the blood during febrile episodes.

---------------------------------------------------------------

This emerging research has significance for many countries because Borrelia Miyamotoi has been found in a number of countries including England 

 http://lookingatlyme.blogspot.co.uk/2014/07/borrelia-miyamotoi-found-in-ticks-in.html

Wednesday, 3 June 2015

CHRONIC LYME DISEASE - INEFFECTIVE KILLING OF BORRELIA BURGDORFERI PERSISTER CELLS?

Identification of new compounds with high activity against stationary phase Borrelia burgdorferi from the NCI compound collection

Jie Feng, Wanliang Shi, Shuo Zhang and Ying Zhang
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
Correspondence: Y Zhang, E-mail: yzhang@jhsph.edu
Received 20 March 2015; Revised 22 April 2015; Accepted 8 May 2015
Top

ABSTRACT

Lyme disease is the leading tick-borne disease in the USA. Whereas the majority of Lyme disease patients with early disease can be cured with standard treatment, some patients suffer from chronic fatigue and joint and muscular pain despite treatment, a syndrome called posttreatment Lyme disease syndrome. Although the cause is unclear, ineffective killing ofBorrelia burgdorferi persisters by current Lyme disease antibiotics is one possible explanation. We took advantage of our recently developed high-throughput viability assay and screened the National Cancer Institute compound library collection consisting of 2526 compounds against stationary phase B. burgdorferi. We identified the top 30 new active hits, including the top six anthracycline antibiotics daunomycin 3-oxime, dimethyldaunomycin, daunomycin, NSC299187, NSC363998 and nogalamycin, along with other compounds, including prodigiosin, mitomycin, nanaomycin and dactinomycin, as having excellent activity against B. burgdorferi stationary phase culture. The anthracycline or anthraquinone compounds, which are known to have both anti-cancer and antibacterial activities, also had high activity against growing B. burgdorferi with low minimum inhibitory concentration. Future studies on the structure–activity relationship and mechanisms of action of anthracyclines/anthraquinones are warranted. In addition, drug combination studies with the anthracycline class of compounds and the current Lyme antibiotics to eradicate B. burgdorferi persisters in vitro and in animal models are needed to determine if they improve the treatment of Lyme disease.


'Of the 2526 compounds in the NCI compound library collection tested, 237 were found to have higher activity against B. burgdorferi persisters than doxycycline and amoxicillin in the primary screen.'

'In summary, we identified the anthracycline class of compounds including daunomycin, daunomycin 3-oxime, dimethyldaunomycin, NSC299187, NSC363998, and nogalamycin along with some other compounds, including prodigiosin, mitomycin, nanaomycin, and dactinomycin, as having excellent activity against both the non-growing stationary phase and growing B. burgdorferi cultures. The structure–activity relationship and mechanisms of action of the anthracycline/anthraquinone class of compounds against B. burgdorferi persisters should be addressed in future studies. In addition, drug combination studies with the anthracycline class of compounds and the current Lyme antibiotics are required to assess whether they improve treatment of Lyme disease in animal models and in patients.'


This latest study follows on from earlier studies posted about 

Earlier posts on work by Prof Zhang

Prof Ying Zhang is due to present at this year's LDA conference

Other interesting research on treating Borrelia persister cells by Prof Kim Lewis  

Friday, 29 May 2015

BORRELIA BURGDORFERI - LYME DISEASE FORMS DRUG TOLERANT PERSISTER CELLS

Borrelia burgdorferi, the causative agent of Lyme disease, forms drug-tolerant persister cells.

  1. Kim Lewis1*
+Author Affiliations
  1. 1Department of Biology, Northeastern University, Boston, Massachusetts, USA
  2. 2Department of Medicine, Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, Massachusetts, USA.

ABSTRACT

Borrelia burgdorferi is the causative agent of Lyme disease, which affects an estimated 300,000 people annually in the US. When treated early, the disease usually resolves, but left untreated, can result in symptoms such as arthritis and encephalopathy. Treatment of the late stage disease may require multiple courses of antibiotic therapy. Given that antibiotic resistance has not been observed for B. burgdorferi, the reason for the recalcitrance of late stage disease to antibiotics is unclear. In other chronic infections, the presence of drug-tolerant persisters has been linked to recalcitrance of the disease. In this study, we examined the ability of B. burgdorferi to form persisters. Killing of growing cultures of B. burgdorferiwith antibiotics used to treat the disease was distinctly biphasic, with a small subpopulation of surviving cells. Upon regrowth, these cells formed a new subpopulation of antibiotic-tolerant cells, indicating that these are persisters rather than resistant mutants. The level of persisters increased sharply as the culture transitioned from exponential to stationary phase. Combinations of antibiotics did not improve killing. Daptomycin, a membrane-active bactericidal antibiotic, killed stationary phase cells, but not persisters. Mitomycin C, an anti-cancer agent that forms adducts with DNA, killed persisters and eradicated both growing and stationary cultures of B. burgdorferi. Finally, we examined the ability of pulse-dosing an antibiotic to eliminate persisters. After addition of ceftriaxone, the antibiotic was washed away, surviving persisters were allowed to resuscitate, and antibiotic was added again. Four pulse-doses of ceftriaxone killed persisters, eradicating all live bacteria in the culture.
http://aac.asm.org/content/early/2015/05/20/AAC.00864-15.abstract

Earlier post with vimeo of Prof Lewis as well as CDC Webinar  

Good to see Dr Linden T Hu working with Prof Lewis - Dr. Linden Hu, Tufts University
Borrelia burgdorferi Persistence: Consensus and Controversy – where do we go from here? This was presented in CDC Webinar on persistence see link above.


Researchers’ discovery may explain difficulty in treating Lyme disease - 

This is the first time, we think, that pulse-​​dosing has been pub­lished as a method for erad­i­cating the pop­u­la­tion of a pathogen with antibi­otics that don’t kill dor­mant cells,” Lewis said. “The trick to doing this is to allow the dor­mant cells to wake up.”

He added: “This gives you an idea that you could, in prin­ciple, estab­lish a sim­ilar reg­i­ment for treating patients for this and other chronic diseases.”

Other videos of Prof Lewis Principles of Antibiotic Discovery - Kim Lewis 

Uncultured Bacteria - Kim Lewis 
https://www.youtube.com/watch?v=-ojRvlwanSA


Prof Lewis featured in a recent BBC documentary on Panorama on his research into finding new antibiotics 


Wednesday, 20 May 2015

HEADACHES FOLLOWING TICK BITE - COULD IT BE BARTONELLA?



Published on Apr 2, 2015
Bartonella infection is a recently identified emerging infectious disease associate with both acute and chronic disorders in humans and animals from cat scratch disease and trench fever to symptoms easily misdiagnosed as an autoimmune disorder.

Video credit: NC Museum of Natural Sciences http://naturalsciences.org/

Healthy teen boy develops debilitating #headaches. Fortunately his mother is a veterinarian.